The invention relates to an apparatus and a method for detecting a substance in a sample, particularly for detecting and measuring the concentration of a substance such as glucose in body fluid or tissue.
Insulin dependent diabetics have to monitor their blood glucose concentrations at regular intervals. At present, this is mostly done by taking a blood sample and analyzing it outside the patient""s body. Patients who monitor their blood glucose level themselves use a finger lance to obtain a drop of blood which is applied to a reagent strip for analyzing. Naturally this process causes pain and discomfort. There have been various attempts, therefore, to detect blood glucose concentrations in vivo.
EP-A-282234 proposes in vivo detection of glucose in the blood stream by infrared spectroscopy using a laser beam penetrating a person""s skin. The wavelength of the laser beam is selected in the near-infrared (NIR) range of 0.76 to 2.5 xcexcm.
As explained by H. A. Mac Kenzie et al. in Phys. Med. Biol. 38 (1993) 1911-1922 and in Clinical Chemistry 45:9 (1999) 1587-1595, the near-infrared range and in particular the wavelength region of 1 to 2 xcexcm is preferred for non-invasive blood glucose measurement as the absorption of light of other wavelengths in the human skin is too large for the light to penetrate to a suitable depth for interaction with blood. In Medical and Biological Engineering and Computing, May 1993, 284 to 290, Mac Kenzie et al. report also the use of the mid-infrared (MIR) wavelength region of 2.5 to 25 xcexcm for glucose measurements. But due to the very low skin transmission at these wavelengths, they have not measured glucose concentrations in vivo. The mid-infrared light source used is a CO2 laser and the glucose concentration is obtained by measuring the absorption coefficient in the sample at a certain wavelength and relating it to the absorption coefficient of distilled water at the same wavelength.
In the above-discussed prior art, the optical absorption coefficient is measured through the photoacoustic effect: optical absorption of infrared radiation leads to molecular resonance such as vibrational modes of Cxe2x80x94O bonds in glucose; when de-excitation occurs through nonradiative molecular transitions, the sample is locally heated, producing a temperature gradient and a material strain. The strain can be detected by an acoustic sensor. Localized heating and expansion of the material from a pulse of light produces a pulse of an acoustic wave.
The use of a photoacoustic detector for in vivo measuring blood glucose levels is disclosed in WO 91/18548. In this prior art, infrared light of two wavelengths in the MIR region is applied at two different locations to a person""s skin. One wavelength is selected such that blood glucose shows a specific absorption and the other wavelength is selected such that there is no specific absorption by glucose. An acoustic detector detects the pressure difference between the locations where the different wavelengths are applied.
A simple arrangement for measuring blood glucose levels by infrared transmission through a person""s finger is disclosed in U.S. Pat. No. 5,313,941. This arrangement uses a filament infrared source and silicon photodetectors with filters to select a certain wavelength band from the source.
None of the above techniques has yet led to a practically usable device for noninvasive detection of glucose. At infrared intensities which are practically usable without unduly heating or even burning a person""s skin, all the known techniques are not sensitive and reliable enough or are too bulky for daily use.
It is an object of the invention to provide a simple and reliable apparatus and method for noninvasive detection of a substance in a sample.
This object is solved by the apparatus and the method set forth in the independent claims. The dependent claims are directed to further embodiments of the invention.
Substances of interest such as glucose have covalent bonds with fundamental resonance frequencies in the mid-infrared region of the light spectrum, i.e. at frequencies corresponding to infrared light wavelengths from 2.5 to 25 xcexcm (wavenumbers of 4000 to 400 cmxe2x88x921). Hence, the mid-infrared region of the absorption spectrum of these substances contains relatively narrow absorption lines specific to each individual substance. This is an advantage over the use of the near infrared region at wavelengths from 0.76 to 2.5 xcexcm where infrared absorption by the substances of interest is due to harmonics of the oscillating molecular bonds and absorption bands are broader, overlap each other, have smaller and wider peaks and it is thus more difficult to attribute absorption to the substance to be detected.
What was previously believed a disadvantage of noninvasive detection of substances such as glucose in body fluids or tissue by mid infrared spectroscopy, namely the high parasitic absorption of mid infrared light by water is overcome by detecting absorption through the photoacoustic effect and by using laser light at a plurality of discrete wavelengths.
The use of the photoacoustic effect for detecting infrared light absorption has the advantage of enabling detection of the substance in a noninvasive technique from within a sample even if light absorption by the sample is too high to allow detecting the substance from transmitted or reflected light.
Irradiating the sample with laser light of at least two distinct and discrete wavelengths at a peak or valley in the absorption spectrum of the substance to be detected in the sample has two effects. Firstly, these are the wavelengths where the absorbance is less dependent on wavelength variations and on a possible shift in the absorption lines due to unknown other components in the sample. Secondly, unnecessary heating of the sample by light of other wavelengths such as in conventional spectroscopy with infrared sources emitting a broad range of wavelengths is avoided. The admissible light intensity can therefore be concentrated on the discrete wavelengths which offer the most accurate results.
The features of the present invention improve the accuracy of the detection. A measurement at the same location of the sample in accordance with the present invention avoids errors from sample inhomogeneities.
A preferred laser device includes a semiconductor laser having a quantum well structure. Quantum well structures are made by alternating layers of different semiconductor material and form energy sub-bands wherein sub-band transitions are used for operation of the laser. The transition energy depends on the semiconductor material and on the layer thickness and can be adjusted to meet the wavelength requirements of the invention. One such laser device is the quantum cascade laser. A description of the quantum cascade laser can be found in J. Faist: xe2x80x9cQuantum Cascade Laserxe2x80x9d Science, 264 (1994) 553 to 556.
The present invention relates to the measurement of the concentration of the detected substance.
An embodiment of the present invention will now be described with reference to the drawings.